ABSTRACT The goal of this project is to study the role of the host SK1-S1P pathway in controlling the infection by Cryptococcus neoformans (Cn). In previous studies, we identified that the host sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) are critical for the formation of the lung granuloma against Cn.1-3 Our studies in mice are supported by the observation that patients treated with FTY720 (Fingolimod) for multiple sclerosis4 (MS) developed cryptococcosis.5-9 When we administered FTY720 to our model of mouse granuloma, Cn lung infection reactivated and fungal cells disseminated from the lung to the brain tissue, eventually killing the animals. Intriguingly, this effect was not observed with BAF312 or AUY954 treatment. FTY720 is a sphingosine analog that, once phosphorylated, mimics S1P and binds to S1P receptors S1Pr1, S1Pr3 and S1Pr510 whereas the un-phosphorylated form of BAF312 or AUY954 binds to S1Pr1 and S1Pr5,11 or only to S1Pr1,12 respectively. These results suggest that SK1-S1P may regulate the containment of Cn cells within the lung granuloma through the inhibition of a specific S1P receptor(s), such as S1Pr3, as this is one of the receptors targeted by FTY720 but not by the other compounds. Because these drugs all induce a severe lymphopenia by blocking the egress of lymphocytes from lymph nodes,13-15 our studies also suggest that lymphopenia may not be sufficient for Cn infection to reactivate. Based on these findings, we hypothesize that the action of S1P on S1Pr regulates the host cellular immunity against Cn and that blocking S1Pr3 is detrimental for the host and may lead to reactivation of cryptococcosis during lymphopenia. Thus we will: 1) determine how SK1-S1P regulates the formation of Cn granuloma; and 2) define the host immune response controlled by SK1-S1P that protects against the reactivation of Cn granuloma.